Phenacyl bromides revisited: Facile synthesis of some new pyrazoles, pyridazines, and their fused derivatives

Article abstract of DOI:10.1002/jhet.1664

Phenacylmalononitriles 8a, 8b react with hydrazines under dry conditions to afford the pyrazole derivatives 9a, 9b, 9c, 9d and in refluxing dioxane to afford the pyrazolo[3,4-c]pyridazine derivatives 11a, 11b, 11c, 11d and the pyridazine-6-imine derivativ

Full text of DOI:10.1002/jhet.1664

March 2014
Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles,
Pyridazines, and Their Fused Derivatives
475
a
a
b
c
*
Fathy M. Abdelrazek, Hamdi M. Hassaneen, Ekhlass M. Nassar, and Anna Jager
aChemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
bChemistry Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Heleopolis, Cairo, Egypt
cInstitute of Organic Chemistry, TU-Dresden, Dresden 01062, Germany
*
E-mail: prof.fmrazek@gmail.com
Received November 7, 2011
DOI 10.1002/jhet.1664
Published online 20 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Phenacylmalononitriles 8a,b react with hydrazines under dry conditions to afford the pyrazole derivatives
9a–d and in refluxing dioxane to afford the pyrazolo[3,4-c]pyridazine derivatives 11a–d and the pyridazine-
6-imine derivatives 12a–d. Compounds 12a,b were transformed into their oxo analogs 13a,b upon reflux
in ethanolic HCl, whereas 12c,d were transformed into the furan derivatives 14a,b under the same reaction
conditions (reflux in ethanolic HCl). Compounds 8a,b could be transformed directly into the benzoyl-pyrazole
derivatives 16a–d upon coupling with diazotized aromatic amines in pyridine. The structures of the new
compounds were substantiated by elemental analyses and spectral data as well as x-ray crystallographic analysis.
Plausible mechanisms for the unexpected transformations are suggested.
J. Heterocyclic Chem., 51, 475 (2014).
INTRODUCTION
malononitrile 3 under dry conditions will lead to the desired
condensation products 5b,c (Scheme 1).
In the past few years, we have been involved in a program
aimed at the synthesis of some new heterocyclic systems
of biological interest to be tested as biodegradable
agrochemicals [1–5]. In the context of this program, we
have previously reported several syntheses starting from
2-bromo-1-phenylethanone (o-bromoacetophenone) 2a
(obtained from acetophenone 1 by bromination; Fig. 1) [6–9].
Some new pyrrole, pyrazole, and pyridazine derivatives
were required for such biological studies. 2-(2-Bromo-1-
phenylethylidene)-malononitrile derivatives 5b,c seemed
good precursors to fulfill this objective via their reaction
with differently substituted aromatic amines to obtain the
pyrrole derivatives 7 presumably via the intermediates 6 [10]
(Scheme 1).
The parent compound of this series 5a was eventually
obtained via Knoevenagel condensation of acetophenone
1 with malononitrile 3 to afford 2-(1-phenylethylidene)-
malononitrile 4 and then brominating this latter compound
to afford 5a [10] (Fig. 1). Because we already have the bromo
derivatives 2b,c, it was thought that their condensation with
RESULTS AND DISCUSSION
Thus, the reaction between 2b,c and malononitrile 3
was conducted in dry conditions without solvent and was
catalyzed by piperidine; however, after treatment and
purification of the products, we have found that they are
not the desired condensation products 5b,c but rather the
phenacyl malononitrile derivatives 8a,b. The elemental
analyses showed that these products did not show any
bromine content, and their 1H NMR spectra showed gener-
ally the doublet and triplet signals at d = 3.6 (d, 2H) and
4.35 (t, 1H) ppm, respectively. It should be mentioned that
compounds 8a has been previously described in the litera-
ture and was obtained via another route with approximately
the same yield [11].
In spite of not obtaining the desired condensation
products 5b,c, however, the obtained phenacyl malononitrile
derivatives 8a,b seemed also excellent precursors to fulfill
our target via their reaction with hydrazine hydrate and
© 2013 HeteroCorporation

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F. M. Abdelrazek, H. M. Hassaneen, E. M. Nassar, and A. Jager
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Ph
CN
CN
CN
of these spectral as well as elemental analytical data,
the p-substituted 4-phenacyl-3,5-diaminopyrazole struc-
tures 9a–d were assigned to these products. 13C NMR
data of these compounds confirmed these structures.
The mass spectra showed also molecular ion peaks that
fit correctly to these structures (cf. Experimental).
Ph
O
CN
3
4
1
Br2/AcOH
Br2/AcOH
The reaction of 8a,b with hydrazine hydrate was carried
out in refluxing dioxane, and we could isolate two products
in each case (fractional crystallization) with melting points
235 and 290ꢀC and 240 and 293ꢀC, respectively. On the
basis of the analytical and spectral data, the higher mp
products (290 and 293ꢀC) were recognized as the pyrazolo
[3,4-c]pyridazine derivatives 11a,b, whereas the lower
mp products (235 and 240) were recognized as the
tetrahydropyridazine-6-imines 12a,b.
Ph
CN
CN
O
3
Br
Ph
Piperidine,
Br
5a
2a
Figure 1. Synthesis of 2-(2-bromo-1-phenylethylidene) malononitrile.
phenyl hydrazine and the coupling reaction. The results of the
reaction of 8a,b with hydrazine hydrate and phenyl hydrazine
were found to depend on the applied reaction conditions.
Thus, when 8a,b were allowed to react with hydrazine
hydrate and phenyl hydrazine under dry conditions without
solvent at room temperature, the obtained products were
found to be 1:1 adducts. The IR spectrum of the isolated
products showed absorption bands at υmax = 3330, 3220,
3100, and 1660 cmÀ1 corresponding to NH, NH2, and
CO groups, respectively, and no cyano absorption bands
were revealed except in the p-cyano derivatives.
Similarly, compounds 8a,b reacted with phenyl hydrazine
in refluxing dioxane to afford in each case two com-
pounds that were separated and analyzed. They were
found to be the pyrazolo[3,4-c]pyridazine derivatives 11c,d
and the pyridazine-6-imine derivatives 12c,d, respectively
(cf. Experimental).
The IR spectra of the higher mp compounds 11a–d
showed no carbonyl absorptions and only the presence of
NH2 and NH absorption bands at υmax = 3320–3150 cmÀ1
in 11a,b, but no NH bands were revealed in 11c,d. The
1H NMR spectra of 11a–d revealed generally a singlet
(2H) at d = 2.4 ppm and two aromatic doublets (4H) at
d = 7.45–7.85 ppm. Compounds 11a,b displayed, in addi-
tion, a D2O exchangeable singlets (1H) at d = 8.50 and
11.6 ppm attributable to two NH protons, but the aromatic
integration was 14H in case of 11c,d with no signals
because of NH protons.
1
The H NMR spectrum of the isolated product revealed
a singlet (2H) at d = 3.60 ppm and a singlet (1H, D2O
exchangeable) at d 11.20 and 10.45 ppm because of NH
in the derivatives obtained from 8a,b with hydrazine,
whereas this NH signal disappeared in the derivatives
obtained from 8a,b with phenyl hydrazine. On the basis
Scheme 1. Synthesis of compounds 8, 9, 10, 11 and 12.
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Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles,
Pyridazines, and Their Fused Derivatives
The IR spectra of the lower mp products 12a–d
revealed, generally, absorption bands at υmax = 3280,
3190, and 2231 cmÀ1, attributable to NH and CN groups,
respectively, and no carbonyl absorption bands appeared.
with phenyl hydrazine under the same conditions to afford
dark orange products that were formulated as the phenyl
hydrazones 10c,d. These were also successfully cyclized into
11c,d, respectively. The identity of the compounds was
deduced from their melting points and TLC analysis.
1
The H NMR spectra of these reaction products are in
complete agreement with the assigned structures. A further
support for this structural assignment was gained from the
13C NMR spectrum of 12a that showed signals at d = 22.54
(t), 25.84 (d), 115.30 (s), and 166.54 (s) attributable to
methylene, methine, cyano, and the imine carbon atoms,
respectively, beside the other expected signals because of
the other carbons (cf. Experimental). The mass spectra of
these products showed their correct molecular ion peaks.
On the basis of the aforementioned data, the imino-pyridazine
structures 12a–d were confirmed for these products
(cf. Experimental; Scheme 1).
It seems that in refluxing dioxane, two competitive reac-
tions are working: first is the cycloaddition of hydrazine or
phenyl hydrazine to the two cyano groups of 8 to afford the
4-phenacyl-3,5-diaminopyrazole 9a–d that undergoes an
in situ condensation with hydrazine hydrate or phenyl
hydrazine to afford the hydrazone intermediates 10a–d,
which in its role undergoes cyclization with elimination
of ammonia via the nucleophilic attack of the hydrazone
NH2 or PhNH on the ring amino group to give 11a–d.
Second is the condensation of hydrazine hydrate or phenyl
hydrazine with the carbonyl group of 8 followed by
addition of the hydrazone NH2 or PhNH to one of the
cyano groups to afford 12a–d.
This behavior of 8a,b towards hydrazines is in agree-
ment with our previously reported behavior of phenacyl
malononitrile towards the same reagents [12].
Compounds 12a–d were refluxed in ethanol/conc. HCl
mixture (4:1 by volume) aiming to transform them to the
corresponding pyridazinone derivatives 13a–d (Scheme 2).
However, only 12a,b (R = H; obtained from hydrazine)
could undergo this transformation, and compounds 13a,b
were obtained. Under these conditions, compounds 12c,d
afforded light brown products. The IR spectrum of
these products did not show any carbonyl absorption
band, but absorption bands at υmax = 3010–2280 and 2226
corresponding to NH2 and CN groups were revealed. The
mass spectra of these two products showed molecular ion
peaks at m/z = 213 and 209 (M+ À 1 and M+). These data
correspond to the molecular masses of 12c,d after elimina-
tion of phenyl hydrazine. On the basis of the aforementioned
data, the furan structures 14a,b were thus suggested for
1
these products. The H NMR spectrum of 14a revealed
broad singlets at d = 3.92 ppm (2H, D2O exchangeable)
attributed to NH2 and d = 7.30 ppm integrated for 1H
(furan H) beside two doublets in the aromatic region. The
1H NMR spectrum of 14b revealed the furan proton at the
same position (d = 7.3 ppm) but the NH2 at d = 7.9 ppm.
The 13C NMR data of these products showed the four
carbons of furan beside the other signals at their expected posi-
tions. This unexpected formation of these furan derivatives
urged us to have an X-ray for any of these products, and
luckily, we could obtain it for 14a that showed unambiguously
the furan structure (Fig. 2) [13,14].
To prove this assumption, compounds 9a,b were
allowed to react with hydrazine hydrate in refluxing dioxane,
and we could obtain the hydrazone compounds 10a,b as
orange colored products. Refluxing these latter compounds
in ethanolic sodium ethoxide furnished their cyclization to
afford 11a,b, and analogously, 9c,d were allowed to react
Scheme 2. Synthesis of the pyridazines 12 and 13 and the furans 14.
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F. M. Abdelrazek, H. M. Hassaneen, E. M. Nassar, and A. Jager
Vol 51
C11
C2
C3
N13
C10
C9
C13
O12
C1
C6
C4
O5
C8
C7
C12
N14
Figure 2. X-ray crystallographic structure of the furan derivative 14a [13,14]. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
A plausible mechanism for the transformation of 12c,d
to 14a,b is depicted in Scheme 2. It is assumed to proceed
via initial tautomerization of the pyridazine rings 12c,d
under the effect of HCl to give the intermediates A
followed by hydrolytic ring opening to afford the
intermediates B. These intermediates B in their role
undergo recyclization with loss of phenyl hydrazine to
afford the furan derivatives 14a,b. This behavior is
observed only in case of 12c,d because the phenyl ring
presumably stabilizes and facilitates the elimination of
phenyl hydrazine. The furan derivative 14a was obtained
via an alternative route by refluxing 8a in ethanol catalyzed
by triethylamine [11].
in complete agreement with the pyrazole structures 16a–d
that were assigned for these products. Furthermore, the
13C NMR spectrum of 16a as a representative example
revealed 14 C signals that are applicable to this structure
(cf. Scheme 3 and Experimental).
EXPERIMENTAL
Melting points were determined on an electrothermal (9100)
apparatus (Kleinfeld, Gehrden, Germany) and are uncorrected.
IR spectra were recorded as KBr pellets on a Perkin Elmer 1430
1
spectrophotometer (Perkin Elmer, Norwalk, CT). The H NMR
and 13C NMR spectra were taken on a Varian Gemini 300 MHz
spectrometer (Varian, Oxford, UK) in DMSO-d6 using TMS as
internal standard, and chemical shifts are expressed in d (ppm)
values. Mass spectra were taken on a Shimadzu GCMS-GB
1000 PX (Shimadzu, Kyoto, Japan) (70 eV). Elemental analyses
were carried out by the Microanalytical Center at Cairo University.
The X-ray crystallography as well as a considerable part of the spec-
tra were carried out in the Institute of Organic Chemistry, Technical
University of Dresden, Germany.
Aroyl pyrazoles are also interesting compounds from the
point of view of their biological activity studies as well as
their further transformations [15]. The obtained phenacyl
malononitriles 8a,b were coupled with aromatic diazonium
salts (phenyl- and p-chlorophenyl-) in pyridine solution to
afford bright colored compounds. It was thought that we
have obtained the hydrazo derivatives 15a–d. However,
1
Preparation of the phenacyl malononitrile derivatives
the H NMR spectra of these products did not reveal any
8a,b.
A mixture of the respective o-bromoacetophenone
singlet signals that can be attributed to a methine proton
or the hydrazone proton. Therefore, we had the impression
that our obtained products are the already cyclized pyrazole
derivatives 16a–d. All analytical and spectral data were
derivative 2b or 2c (100 mmol) and malononiotrile 3 (6.6 g;
100 mmol) was warmed under dry conditions on a water
bath untill a homogeneous solution is obtained and then
allowed to cool to room temperature. Piperidine (8.50 g,
Scheme 3. Synthesis of the pyrazoles 16.
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March 2014
479
Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles,
Pyridazines, and Their Fused Derivatives
100 mmol) was added portionwise to this solution with
shaking; each portion is being added after the vigorous
reaction and evolution of fumes have ceased. After complete
addition, the reaction mixture was heated on a boiling water
bath for 1 h, and then allowed to stand overnight. The
crystalline products thus obtained were triturated with ethanol,
filtered off, and then recrystallized from ethanol.
C18H15N5O (317.34): C, 68.13; H, 4.76; N, 22.07. Found: C,
68.18; H, 4.80; N, 22.27.
The reaction of phenacyl-malononitriles 8a,b with hydrazines
in solution: synthesis of 11a–d and 12a–d. A solution of 8a
or 8b (0.01 mol) and hydrazine hydrate or phenyl hydrazine
(0.01 mol) in 25 mL of dioxane was refluxed for 2 h. The
reaction mixture was allowed to cool to room temperature.
The solid precipitate was filtered off, boiled in ethanol where a
part dissolved, filtered while hot, and left to recrystallize. The
insoluble part was recrystallized from DMF/dioxane mixture
(1:1) and identified as 11a–d. The precipitated part from ethanol
was identified as 12a–d. Compounds 11a–d/12a–d were found
to be approximately 1/1 in each case.
2-[2-(4-Methoxyphenyl)-2-oxo-ethyl]-malononitrile 8a. Light
yellow crystals: yield (18.0g, 84%); mp 188–189ꢀC (Lit. [11]
191–192ꢀC); υmax = 2257 (CN), 1684 (CO) cmÀ1; m/z = 213
[M+ À 1]. dH = 3.60 (d, 2H, CH2; J = 4.1 Hz), 3.85 (s, 3H, CH3),
4.35 (t, 1H, CH; J = 4.1Hz), 6.90 and 7.85 (2d, 4H, Ar-H;
J=7.15Hz). dC = 17.77 (d, CH), 39.12 (t, CH2), 55.65 (q, CH3)
112.52 (s, CN), [114.31 (d), 130.66 (d), 131.33 (s), 164.79 (s) Ph
Carbons], 189.80 (s) (C═O). Anal. Calcd for C12H10N2O2 (214.22):
C, 67.28; H, 4.71; N, 13.08. Found: C, 67.35; H, 4.82; N, 13.25.
2-[2-(4-Cyanophenyl)-2-oxo-ethyl]malononitrile 8b. Light
coffee brown crystals: yield (17.8g, 85%); mp 180–182ꢀC;
5-(4-Methoxyphenyl)-4,7-dihydro-2H-pyrazolo[3,4-c]pyridazin-
3-yl amine 11a. zDirty yellow crystalline solid, yield (0.90 g, 75%)
mp 290–291ꢀC. υmax = 3305, 3215, 3138, 3130 (NH2 and NH) cmÀ1
;
m/z= 243 [M+]. dH =2.40–2.48 (s, 2H, CH2), 3.68 (s, 3H, CH3), 6.80
(br s, 2H, NH2), 7.45–7.82 (2d, 4H, Ar-H; J=7.20 Hz), 8.54 (br s,
1H, NH), 11.63 (br s, 1H, NH). d = 15.48 (t), 55.90 (q), 89.32
(s), 114.15(d), 123.63 (s), 130.4 (d), 132.25 (s), 152.10 (s), 155.65
(s), 164.85 (s). Anal. Calcd for C12H13N5O (243.26): C, 59.25; H,
5.39; N, 28.79. Found C, 59.35; H, 5.24; N, 28.85.
υ
max = 2261 (CN), 2229 (CN), 1691 (CO) cmÀ1; m/z = 209 [M+].
dH = 4.12 (d, 2H, CH2; J = 4.0 Hz), 5.15 (t, 1H, CH; J = 4.0 Hz),
8.03 and 8.20 (2d, 4H, Ar-H; J = 7.15 Hz). dC = 17.89 (d, CH),
39.08 (t, CH2), 114.20 (s, CN), 116.10 (s, CN), [118.14
(s), 128.84 (d), 132.78 (d), 137.90 (s) Ph Carbons], 193.95 (s)
(C═O). Anal. Calcd for C12H7N3O (209.20): C, 68.89; H, 3.37;
N, 20.09. Found: C, 68.75; H, 3.35; N, 20.19.
Preparation of 3,5-diaminopyrazole derivatives 9a–d:
general procedure. A mixture of each of 8a,b (0.01 mol) and
hydrazine hydrate or phenyl hydrazine (0.015 mol) is warmed
under dry conditions on a water bath where a vigorous reaction
took place. Few drops of triethylamine may be added to activate
the reaction. The solid masses formed on standing at room
temperature were triturated with ethanol and then poured onto
cold water and acidified by few drops of conc. HCl. The solid
products so formed were filtered off and recrystallized from
ethanol/dimethylformamide (DMF) mixture (4:1).
4-(3-Amino-4,7-dihydro-2H-pyrazolo[3,4-c]pyridazin-5-yl)
benzonitrile 11b. Dirty yellow crystalline solid, yield (0.87 g,
73%) mp 293–294ꢀC. υmax = 3325, 3220, 3135, 3132 (NH2 and
NH), 2225 (CN) cmÀ1; m/z = 238 [M+]. dH = 2.42–2.46 (s, 2H,
CH2), 7.47–7.85 (2d, 4H, Ar-H; J = 7.18 Hz), 8.35 (br s, 2H,
NH2), 8.55 (br s, 1H, NH), 11.65 (br s, 1H, NH). Anal. Calcd
for C12H10N6 (238.25): C, 60.50; H, 4.23; N, 35.27. Found
C, 60.56; H, 4.32; N, 35.20.
5-(4-Methoxyphenyl)-2,7-diphenyl-4,7-dihydro-2H-pyrazolo
[3,4-c]pyridazin-3-yl amine 11c.
Brown crystalline solid,
yield (1.25 g, 63%) mp 305–307ꢀC. υmax = 3325–3220 (NH2)
cmÀ1; m/z = 395 [M+]. dH = 2.43–2.48 (s, 2H, CH2), 3.72 (s,
3H, CH3), 8.72 (br s, 2H, NH2), 7.25–7.95 (m, 14H, Ar-H).
Anal. Calcd for C24H21N5O (395.46): C, 72.89; H, 5.35; N,
17.71. Found C, 72.95; H, 5.25; N, 17.60.
2-(3,5-Diamino-1H-pyrazol-4-yl)-1-(4-methoxyphenyl)-
ethanone 9a.
Yellow crystals: yield (1.85 g, 75%); mp
236–237ꢀC; υmax = 3332, 3216, 3118 (NH2 and NH), 1658 (CO)
cmÀ1; m/z =242 [M+ À 4]. dH = 3.80 (s, 2H, CH2), 3.90 (s, 3H,
CH3), 7.25 and 7.65 (2d, 4H, Ar-H; J = 7.12 Hz.), 8.52 (br, 4H,
2NH2), 11.20 (s, 1H, NH). Anal. Calcd for C12H14N4O2 (246.27):
C, 58.53; H, 5.73; N, 22.75. Found: C, 58.65; H, 5.60; N, 22.55.
4-[2-(3,5-Diamino-1H-pyrazol-4-yl)-acetyl]-benzonitrile
4-(3-Amino-2,7-diphenyl-4,7-dihydro-2H-pyrazolo[3,4-c]
pyridazin-5-yl)benzonitrile 11d.
Brown crystalline solid,
yield (1.27 g, 65%) mp 312–314ꢀC.
υ
max = 3325–3225
(br, NH2); 2223 (CN) cmÀ1; m/z = 390 [M+]. dH = 2.45–2.49
(s, 2H, CH2), 6.75–8.15 (m, 16H, Ar-H + NH2). Anal. Calcd for
C24H18N6 (390.44): C, 73.83; H, 4.65; N, 21.52. Found
C, 73.90; H, 4.55; N, 21.40.
9b.
Yellow crystals: yield (1.64 g, 68%); mp 253–255ꢀC;
υ
max = 3335, 3226, 3078 (NH2 and NH), 2225 (CN), 1678
3-Imino-6-(4-methoxyphenyl)-2,3,4,5-tetrahydropyridazine-
4-carbonitrile 12a. Pale yellow crystalline solid, yield (0.78 g,
69%) mp 235–236ꢀC. υmax = 3280, 3190 (NH) and 2231 (CN)
cmÀ1; m/z = 228 [M+]. dH = 1.75–1.80 (d, 2H, CH2; J = 3.6 Hz),
2.40–2.52 (t, 1H, CH; J = 3.6 Hz), 3.92 (s, 3H, CH3), 7.42 (s, 1H,
ring NH), 7.44–7.58 (2d, 4H, Ar-H; J = 7.14Hz), 11.45 (s, 1H,
═NH). dc = 22.54(t), 25.84(d), 54.95(q), 114.54(d), 115.30(s),
123.75(s), 130.16(d), 155.73(s), 163.75(s), 166.54(s). Anal. Calcd
for C12H12N4O (228.25): C, 63.15; H, 5.30; N, 24.55. Found C,
63.12; H, 5.35; N, 24.62.
(CO) cmÀ1; m/z = 241 [M+]. dH = 3.60 (s, 2H, CH2), 4.65
(s, 2H, NH2) 7.40 and 7.80 (2d, 4H, Ar-H; J = 7.10 Hz),
10.30 (s, 2H, NH2), 10.45 (s, 1H, NH). Anal. Calcd for
C12H11N5O (241.25): C, 59.74; H, 4.60; N, 29.03. Found:
C, 59.60; H, 4.65; N, 29.20.
2-(3,5-Diamino-1-phenyl-1H-pyrazol-4-yl)-1-(4-methoxy-
phenyl)-ethanone 9c. Yellow crystals: yield (2.45 g, 76%);
mp 212–213ꢀC; υmax = 3329–3115 (NH2), 1660 (CO) cmÀ1
.
m/z = 322 [M+]. dH = 3.62 (s, 2H, CH2), 3.91 (s, 3H, CH3),
7.15–7.65 (m, 9H, Ar.H), 8.1 (br, 2H, NH2), 8.17 (br,
2H, NH2). Anal. Calcd for C18H18N4O2 (322.36): C, 67.07;
H, 5.63; N, 17.38. Found: C, 67.00; H, 5.55; N, 17.50.
6-(4-Cyanophenyl)-3-imino-2,3,4,5-tetrahydropyridazine-4-
carbonitrile 12b.
Brownish yellow crystalline solid, yield
(0.75 g, 67%) mp 240–242ꢀC. IR: υmax = 3283, 3195 (NH),
2224 and 2232 (2CN) cmÀ1; m/z = 223 [M+]. dH = 1.74–1.79
(d, 2H, CH2; J = 3.5 Hz), 2.41–2.53 (t, 1H, CH; J = 3.5 Hz),
7.40 (s, 1H, ring NH), 7.42–7.65 (2d, 4H, Ar-H; J = 7.12 Hz),
11.48 (s, 1H, NH). Anal. Calcd for C12H9N5 (223.23):
C, 64.56; H, 4.06; N, 31.37. Found C, 64.55; H, 4.15; N, 31.25.
4-[2-(3,5-Diamino-1-phenyl-1H-pyrazol-4-yl)-acetyl]-
benzonitrile 9d. Yellow crystals: yield (2.10g, 66%); mp 242–
243ꢀC; υmax =3335–3138 (NH2), 2227 (CN), 1667 (CO) cmÀ1
;
m/z = 317 [M+]. dH = 3.64 (s, 2H, CH2), 7.25–7.80 (m, 9H, Ar-H),
8.15 (br, 2H, NH2), 8.21 (br, 2H, NH2). Anal. Calcd for
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3-Imino-6-(4-methoxyphenyl)-2-phenyl-2,3,4,5-tetrahydro-
afford compounds completely identical with 11a–d, respectively.
The identity of these compounds was inferred from the matching
melting points and IR spectra.
Transformation of 12a,b into 13a,b and of 12c,d into 14a,b.
Compounds 12a–d (0.01 mol) were refluxed in ethanol (15mL)
containing conc. HCl (2mL) for 2 h and then left to cool to room
temperature, poured on crushed ice, and neutralized cautiously
with ammonia solution. The precipitated solids were filtered off,
washed thoroughly with water, and recrystallized from ethanol to
afford 13a,b and 14a,b, respectively.
pyridazine-4-carbonitrile 12c. Yellow crystalline solid, yield
(1.18 g, 78%) mp 238–239ꢀC. υmax = 3198, 3090 (NH), 2234
(CN) cmÀ1; m/z = 304 [M+]. dH = 1.74–1.81 (d, 2H, CH2;
J = 3.6 Hz), 2.41–2.50 (t, 1H, CH; J = 3.6 Hz), 3.82 (s, 3H, CH3),
7.45–7.82 (m, 9H, Ar-H), 11.55 (s, 1H, NH). Anal. Calcd for
C18H16N4O (304.35): C, 71.04; H, 5.30; N, 18.41. Found
C, 71.14; H, 5.37; N, 18.50.
6-(4-Cyanophenyl)-3-imino-2-phenyl-2,3,4,5-tetrahydro-
pyridazine-4-carbonitrile 12d.
Dirty yellow crystalline solid,
yield (1.12 g, 75%) mp 242–243ꢀC. υmax = 3215, 3130 (NH), 2226
and 2235 (2CN) cmÀ1; m/z = 299 [M+]. dH =1.76–1.82 (d, 2H,
CH2; J = 3.5 Hz), 2.40–2.48 (t, 1H, CH; J= 3.5 Hz), 7.47–7.85 (m,
9H, Ar-H), 11.63 (s, 1H, NH). Anal. Calcd for C18H13N5 (299.33):
C, 72.23; H, 4.38; N, 23.40. Found C, 72.28; H, 4.35; N, 23.45.
Alternative preparation of 11a–d. a) Preparation of the
6-(4-Methoxyphenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-
carbonitrile 13a. Orange crystalline solid, yield (1.95 g, 85%)
mp 240–242ꢀC. υmax = 3215, 3138 (NH), 2228 (CN), 1678
(C═O) cmÀ1; m/z = 229 [M+]. dH = 1.78–1.82 (d, 2H, CH2;
J = 3.5 Hz), 3.43–3.55 (t, 1H, CH; J = 3.5 Hz), 3.85 (s, 3H, CH3),
7.43 (s, 1H, ring NH), 7.45–7.78 (2d, 4H, Ar-H; J = 7.14 Hz).
dc = 26.94 (t), 35.96 (d), 55.92 (q), 114.58 (d), 116.32 (s), 123.62
(s), 130.21 (d), 155.63 (s), 163.95 (s), 181.56 (s). Anal. Calcd for
C12H11N3O2 (229.23): C, 62.87; H, 4.84; N, 18.33. Found C,
62.85; H, 4.80; N, 18.40.
hydrazones 10a–d.
A solution of the p-substituted 4-
phenacylpyrazole derivatives 9a,b (0.01 mol) with hydrazine
hydrate (0.01 mol) and of the p-substituted 4-phenacyl-1-
phenylpyrazole derivatives 9c,d (0.01 mol) with phenyl
hydrazine (0.01 mol) in 30 mL of ethanol was refluxed for 2 h
where solid orange precipitates appeared. The reaction mixture
was then left to cool to room temperature, filtered off, and
recrystallized from ethanol/DMF to afford orange yellow crystals
that were identified as the hydrazones 10a,b and the phenyl
hydrazones 10c,d, respectively.
4-[2-Hydrazono-2-(4-methoxyphenyl)-ethyl]-1H-pyrazole-
3,5-diamine 10a. Orange crystalline solid, yield (1.85 g, 71%)
mp 172–174ꢀC. υmax = 3327, 3225, 3142, 3038 (NH2 and NH)
cmÀ1; m/z = 260 [M+]. dH = 2.65 (s, 2H, CH2), 3.85 (s, 3H,
CH3), 5.64 (br s, 4H, 2NH2), 6.78–8.18 (m, 6H, Ar-H + NH2),
11.85 (s, 1H, NH). Anal. Calcd for C12H16N6O (260.30):
C, 55.37; H, 6.20; N, 32.29. Found C, 55.45; H, 6.10; N, 32.14.
4-[2-(3,5-Diamino-1H-pyrazol-4-yl)-1-hydrazonoethyl]-
benzonitrile 10b. Orange crystalline solid, yield (1.76 g, 69%)
mp 176–177ꢀC. υmax = 3330, 3226, 3143, 3067 (NH2 and NH)
cmÀ1; m/z = 255 [M+]. dH = 2.66 (s, 2H, CH2), 5.68 (br s, 4H,
2NH2), 6.48–7.58 (2d, 4H, Ar-H; J = 7.05 Hz), 8.34 (br s, 2H,
NH2), 11.88 (s, 1H, NH). Anal. Calcd for C12H13N7 (255.28):
C, 56.46; H, 5.13; N, 38.41. Found C, 56.50; H, 5.25; N, 38.12.
4-[2-(4-Methoxyphenyl)-2-(phenyl-hydrazono)-ethyl]-1-phenyl-
6-(4-Cyanophenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-
carbonitrile 13b.
Orange crystalline solid, yield (1.93 g,
86%) mp 258–260ꢀC. υmax = 3225, 3144 (NH), 2225 and 2236
(2CN), 1679 (C═O) cmÀ1; m/z = 225 [M++1]. dH = 1.75–1.79
(d, 2H, CH2; J = 3.4 Hz), 3.45–3.56 (t, 1H, CH; J = 3.4 Hz),
7.45 (s, 1H, ring NH), 7.54–7.82 (2d, 4H, Ar-H; J = 7.12 Hz).
Anal. Calcd for C12H8N4O (224.22): C, 64.28; H, 3.60; N,
24.99. Found C, 64.30; H, 3.60; N, 25.15.
2-Amino-5-(4-methoxyphenyl)-furan-3-carbonitrile 14a.
Yellow crystals: yield (1.67 g, 78%); mp 216–217ꢀC (Lit.
[11] 214–215ꢀC);
υmax = 3008–2289 (NH2), 2226 (CN)
cmÀ1; m/z = 213 [M+ À 1]. dH = 3.85 (s, 3H, CH3), 3.92 (s, 2H,
NH2), 6.9 (d, 2H, Ph; J = 7.20 Hz), 7.30 (s, 1H, Furan H-4), 7.85
(d, 2H, Ph; J=7.20 Hz). dC = 55.62 (t, CH3), 66.35 (s, Fur. C-3),
107.23 (d, Fur. C-4), 115.16 (s, CN), [114.18 (d), 127.96 (s),
130.55 (d), 164.59 (s) Ph Carbons], 142.63 (s, Fur. C-2),
164.95 (s, Fur. C-5). Anal. Calcd for C12H10N2O2 (214.22): C,
67.28; H, 4.71; N, 13.08. Found: C, 67.32; H, 4.72; N, 13.12.
X-ray crystallographic data: yellow crystals, C12H10N2O2
(Mr = 214.2 g*molÀ1), monoclinic, crystal size = 0.21 0.21
*
*
0.07 mm. space group P21/c (No. 14), a = 19.275(1) Ǻ, b = 5.402
(1) Ǻ, c = 9.926(1) Ǻ, a[ꢀ] = 90.00, b[ꢀ] = 99.13 (1), g[ꢀ] = 90.00;
V[Ǻ3] = 1020.4 (2), Z = 4, Dcalc. = 1.394 g*cmÀ3, F(000) = 448 e,
m(Mo Ka) = 0.097 nmÀ1; the final difference Fourier r = 0.18
(À0.19) e ǺÀ3. Max. resolution [sin θ/l]max = 0.61 ǺÀ1/99.6%.
Data were collected using a Bruker Nonius (Bruker, Rheinstetten,
Germany) area detector at T[ꢀC]= À75 (2), with graphite mono-
chromator with Mo Ka radiation (l = 0.71073Ǻ) using the CCD
data collection and SADABS absorption correction method; min.
98.0% max: 99.3%. Total number of reflections collected=16317.
Number of independent reflections are 1873 and were counted with
observed reflections 1519. Rav = 0.032. The final R and R2W = 0.035
and 0.082, respectively.
1H-pyrazole-3,5-diamine 10c.
Dark orange crystalline solid,
yield (2.68 g, 65%) mp 213–215ꢀC. υmax = 3327, 3225, 3142, 3038
(NH2 and NH) cmÀ1; m/z= 412 [M+]. dH = 2.65 (s, 2H, CH2), 3.75
(s, 3H, CH3), 5.64 (br s, 2H, NH2), 6.78–8.28 (m, 16H, Ar-
H+NH2), 12.85 (s, 1H, NH). Anal. Calcd for C24H24N6O (412.49):
C, 69.88; H, 5.86; N, 20.37. Found C, 69.60; H, 5.80; N, 20.55.
4-[2-(3,5-Diamino-1-phenyl-1H-pyrazol-4-yl)-1-(phenyl-
hydrazono)-ethyl]-benzonitrile 10d.
Dark orange crystalline
solid, yield (2.65g, 63%) mp 233–235ꢀC. υmax = 3327, 3225,
3142, 3038 (NH2 and NH) cmÀ1; m/z = 407 [M+]. dH = 2.71
(s, 2H, CH2), 5.66 (br s, 2H, NH2), 6.78–8.28 (m, 16H, Ar-
H + NH2), 12.90 (s, 1H, NH). Anal. Calcd for C24H21N7 (407.47):
C, 69.88; H, 5.86; N, 20.37. Found C, 69.60; H, 5.80; N, 20.55.
b) Cyclization of 10a–d. To a solution of each of 10a–d
(0.005mol) in absolute ethanol (20mL) was added 2 mL of freshly
prepared sodium ethoxide (0.25 g of Na metal dissolved in 10 mL
of ethanol), and the reaction mixture was refluxed for 2 h, and
then left to cool to room temperature and poured on ice cold wa-
ter and acidified with few drops of conc. HCl till neutral. The
solid precipitates thus appeared was filtered off and washed thor-
oughly with cold water, dried, and recrystallized from ethanol to
2-Amino-5-(4-cyanophenyl)-furan-3-carbonitrile 14b.
Brownish yellow crystals: yield (1.67 g, 80%); mp 240–241ꢀC;
υ
max = 3017–2287 (NH2), 2254 and 2226 (2CN) cmÀ1; m/z = 209
[M+]. dH = 7.3 (s, 1H, Furan H-4), 7.58 (d, 2H, Ph; J = 7.19 Hz),
7.78 (d, 2H, Ph; J = 7.19 Hz), 7.90 (s, 2H, NH2). dC = 67.30 (s),
107.81 (s), 111.38 (d), 115.54 (s), 119.01 (s), 122.11 (d), 132.85
(d), 133.25 (s), 139.97 (s), 164.63 (s). Anal. Calcd for C12H7N3O
(209.20): C, 68.89; H, 3.37; N, 20.09. Found: C, 68.95; H, 3.42;
N, 20.00.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2014
481
Phenacyl Bromides Revisited: Facile Synthesis of Some New Pyrazoles,
Pyridazines, and Their Fused Derivatives
The coupling reaction of 8a,b with diazonium salts:
preparation of the pyrazoles 16a–d. Aryl diazonium salts
(0.01 mol) were freshly prepared by adding a solution of
0.01 mol of sodium nitrite in 5 mL of water to a cold solution
of the respective arylamine hydrochloride (aniline or p-chloroaniline
in 5 mL conc. HCl; 0.01 mol) with stirring. The resulting
solutions of the aryl diazonium salts were added to a cold
solution of each of the phenacyl malononitriles 8a,b
(0.01 mol), in pyridine (50 mL). The reaction mixture was
stirred at room temperature for 1 h in each case and then cold
water was added (~100 mL), and to the whole solution was
added conc. HCl dropwise until neutral. The precipitated solids
were filtered off and recrystallized from ethanol/DMF (5:1) to
afford the pyrazoles 16a–d.
(347.76): C, 62.17; H, 2.90; Cl, 10.19; N, 20.14. Found: C, 62.35;
H, 2.68; Cl, 10.32; N, 20.34.
Acknowledgments. F. M. Abdelrazek thanks the Alexander von
Humboldt Foundation (Germany) for granting
a research
fellowship (July 2011); during this time, considerable part of
the analyses and spectra were carried out, and also for the
continuous help and support. Thanks are also due to Professor
Peter Metz, Institute of Organic Chemistry, TU Dresden, for his
repeated invitations and kind hospitality.
5-Amino-3-(4-methoxybenzoyl)-1-phenyl-1H-pyrazole-4-
carbonitrile 16a. Yellow crystals: yield (3.00 g, 79%); mp
222–223ꢀC; υmax = 3022 (NH2), 2222 (CN), 1663 (C═O)
cmÀ1; m/z = 318 [M+]. dH = 3.90 (s, 3H, CH3), 4.78 (s, 2H,
NH2), 6.96 (d, 2H, Ar-H; J = 7.08 Hz), 7.35–7.96 (m, 5H, Ph),
8.40 (d, 2H, Ar-H; J = 7.08 Hz). dC = 56.32 (q), 96.60
(s), 114.42 (d), 115.32 (s), 118.88 (d), 125. 62 (s), 126.22
(d), 129.15 (d), 130.62 (d), 139.42 (s), 142.40 (s), 152.46 (s),
166.54 (s), 186.92 (s). Anal. Calcd for C18H14N4O2 (318.33):
C, 67.91; H, 4.43; N, 17.60. Found: C, 67.90; H, 4.45; N, 17.68.
5-Amino-3-(4-cyanobenzoyl)-1-phenyl-1H-pyrazole-4-
REFERENCES AND NOTES
[1] Abdelrazek, F. M.; Metwally, N. H. Synth Commun 2006,
36, 83.
[2] Abdelrazek, F. M.; Ghozlan, S. A.; Michael, F. A. J Heterocyclic
Chem 2007, 44, 63.
[3] Abdelrazek, F. M.; Metwally, N. H. Synth Commun 2009,
39, 4088.
[4] Abdelrazek, F. M.; Metwally, N. H.; Kassab, N. A.; Sobhy, N.
A.; Metz, P.; Jaeger, A. J Heterocyclic Chem 2010, 47, 384.
[5] Abdelrazek, F. M.; Sharaf, M. F.; Metz, P.; Jaeger, A. J
Heterocyclic Chem 2010, 47, 528.
[6] Abdelrazek, F. M.; Erian, A. W.; Torgoman, A. M. Chem &
Ind (London) 1988, 30.
[7] Abdelrazek, F. M. J Prakt Chem 1990, 332, 479.
[8] Abdelrazek, F. M.; Kandeel, Z. E.; Salah, A. M. Heteroatom
Chem 1995, 6, 77.
[9] Abdelrazek, F. M.; Metwally, N. H. Afinidad 2003, 60, 554.
[10] Süsse, M.; Johne, S. J Prakt Chem 1981, 323, 647; and refer-
ences therein.
[11] Karavan, V. S.; Semenova, S. N.; Schurinova, A. K. J Org
Chem (Russ) 1969, 5, 2161.
[12] Abdelrazek, F. M.; Mohamed, A. M. Afinidad 2008, 65, 56.
[13] Crystallographic data (excluding structure factors) for the
structure 15 reported in this article have been deposited with the
Cambridge Crystallographic Data Centre as a supplementary publication
no. CCDC 848860. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax.: (internat.) + 44 1223/336-033; e-mail: deposit@ccdc.cam.ac.uk].
[14] Keller, E. SCHAKAL 99, A Computer Program for the
Graphic Representation of Molecular and Crystallographic Models;
Universität Freiburg, Germany, 1999.
carbonitrile 16b.
Yellow crystals: yield (2.13 g, 68%);
mp 228–230ꢀC; υmax = 3028 (NH2), 2245 and 2222 (2CN),
1668 (C═O) cmÀ1; m/z = 313 [M+]. dH = 4.82 (s, 2H, NH2),
6.95 (d, 2H, Ar-H; J = 7.06 Hz), 7.33–7.95 (m, 5H, Ph), 8.39
(d, 2H, Ar-H; J = 7.06 Hz). Anal. Calcd for C18H11N5O
(313.31): C, 69.00; H, 3.54; N, 22.35. Found: C, 69.15; H,
3.45; N, 22.30.
5-Amino-1-(4-chlorophenyl)-3-(4-methoxybenzoyl)-1H-
pyrazole-4-carbonitrile 16c.
Yellow crystals: yield
(2.29 g, 65%); mp 156–158ꢀC; υmax = 3032 (NH2), 2221
(CN), 1667 (C═O) cmÀ1; m/z = 318 [M+]. dH = 3.92 (s, 3H,
CH3), 4.79 (s, 2H, NH2), 7.23–7.80 (m, 8H, Ar-H). Anal.
Calcd for C18H13ClN4O2 (352.77): C, 61.28; H, 3.71; Cl,
10.05; N, 15.88. Found: C, 61.35; H, 3.82; Cl, 9.85; N, 15.69.
5-Amino-1-(4-chlorophenyl)-3-(4-cyanobenzoyl)-1H-pyrazole-
4-carbonitrile 16d.
Yellow crystals: yield (2.36 g, 68%); mp
128–130ꢀC; υmax = 3035 (NH2), 2225 and 2253 (2CN), 1672
(C═O) cmÀ1; m/z = 347 and 349 [M+ Æ 1]. dH = 4.85 (s, 2H,
NH2), 6.95–8.30 (m, 8H, Ar-H). Anal. Calcd for C18H10ClN5O
[15] Schepetkin, I. A.; Khlebnikov, A. I.; Quinn, M. T. J Med
Chem 2007, 50, 4928.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet